Nuclear factor kappa B (NF-?B) is a group of dimeric transcription factors that normally regulate immune, inflammatory and cell death responses and is often deregulated in various human cancer cell types. A large body of work over the last two decades has characterized two genetically and biochemically distinct pathways of NF-?B activation, referred to as the canonical and non-canonical pathways. Common to both NF-?B activation pathways is their reliance on 26S proteasomes to degrade/process inhibitor proteins; therefore, these pathways are highly sensitive to proteasome inhibitors, including clinically employed bortezomib. Our lab previously described an atypical mechanism of NF-?B activation, which contrasted with these known pathways by its high resistance to over 10 different proteasome inhibitors, including bortezomib. We have also provided evidence that a significant fraction of NF-?B activity detectable in primary multiple myeloma (MM) and mantle cell lymphoma patient samples is resistant to bortezomib. We further reported that bone marrow stromal cells derived from MM patients', but not normal, marrows produce a soluble factor(s) that further augment NF-?B activity in MM cells to induce bortezomib resistance. We now identified one factor produced by stromal cells that can potently induce NF-?B activation in MM cells in a manner highly resistant to bortezomib. This factor is an extracellular matrix protein that has previously not been linked to NF-?B signaling or MM pathologies. Interestingly, not the full-length version but its fragments are potent inducers of NF-?B. Moreover, there are other proteins in human proteome that contain the conserved domain. Based on these new findings, we hypothesize that there are a family of novel inducers that cause atypical NF-?B activity. This hypothesis will be addressed in two specific aims: to elucidate physiologically relevant forms of this inducer and associated gene signatures (Aim1) and to determine whether other conserved domains can also induce NF-?B signaling (Aim 2). Our study may reveal a potential family of novel NF-?B inducers generated from extracellular matrix proteins that may play key roles in MM drug resistance but also other physiological and pathological processes.